Contributions of Nociresponsive Area 3a to Normal and Abnormal Somatosensory Perception.

Traditionally, cytoarchitectonic area 3a of primary somatosensory cortex (SI) has been regarded as a proprioceptive relay to motor cortex. However, neuronal spike-train recordings and optical intrinsic signal imaging, obtained from nonhuman sensorimotor cortex, show that neuronal activity in some of the cortical columns in area 3a can be readily triggered by a C-nociceptor afferent drive. These findings indicate that area 3a is a critical link in cerebral cortical encoding of secondary/slow pain. Also, area 3a contributes to abnormal pain processing in the presence of activity-dependent reversal of gamma-aminobutyric acid A receptor-mediated inhibition. Accordingly, abnormal processing within area 3a may contribute mechanistically to generation of clinical pain conditions. PERSPECTIVE: Optical imaging and neurophysiological mapping of area 3a of SI has revealed substantial driving from unmyelinated cutaneous nociceptors, complementing input to areas 3b and 1 of SI from myelinated nociceptors and non-nociceptors. These and related findings force a reconsideration of mechanisms for SI processing of pain.

Prospective evaluation of chronic pain disorders and treatments.

BACKGROUND: The incidence of chronic pain is variable among individuals who have sustained traumatic or surgical injury. Also, treatments for pain rarely are effective consistently for a procedure or agent, and no therapies are considered effective for pain that is chronic. NEW METHOD: Difficulties with standard methods for conducting clinical trials call attention to a need for protocols that provide a new understanding of the development of and control over chronic pain. Prospective single-subject research designs can document varieties of pain progression over time for individuals. Subsequent grouping of individuals with common characteristics directs a mechanism-based approach to therapy. RESULTS: Tracking of individuals' pain and associated influences over time is consistent with clinical practice, noting and adapting to changes that occur. COMPARISON WITH EXISTING METHODS: Grouping patients with diverse characteristics and variable effects of therapy is problematic. Conventional evaluation of pain assesses patients with similar injuries or surgery without characterizations of individuals who develop chronic pain or recover over time. Also, classical evaluation of therapies involves comparison of groups receiving treatment or a placebo without characterization of patients with successful and unsuccessful results. CONCLUSIONS: Single-subject prospective studies can inform clinical trials according to individual differences that would be obscured by comparison of groups with unknown variation in characteristics that influence pain and therapeutic effectiveness.

Methodological Considerations for the Temporal Summation of Second Pain.

Temporal summation of second pain (TSSP) is a psychophysical indication of a central pain encoding mechanism, potentially enhanced in pathological pain conditions. Low-frequency repetitive stimulation of unmyelinated (C) nociceptors results in a progressive increase of pain intensity when thermal stimulation intensity remains constant. However, when using different methods of nociceptive delivery to the skin, regularity as well as rate of pain enhancement with repetition varies between experiments. Specifically, repetitive ramping up and down from a neutral to a painful temperature has produced weak and inconsistent pain summation. In contrast, repetitive contact of the skin with a preheated probe has generated substantial pain summation. In the present study, TSSP by the intermittent contact with a preheated thermode and constant contact, ramp and hold methods were compared during 10 iterations of stimulation of glabrous skin of the hand or hairy forearm skin, with an onset to onset interval of 3.3 seconds and stimulus interval of .8 seconds. Significantly greater TSSP was observed for intermittent contact stimulation at both sites (P < .001). Differential activation of myelinated and unmyelinated nociceptors by ramping and tapping may account for different rates of temporal summation of heat pain. PERSPECTIVE: This article presents direct evidence suggesting the constant contact, ramp and hold stimulus may underestimate the level of TSSP. This evidence suggests the re-evaluation of stimulation techniques used for temporal summation tests, especially within clinical models.

The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms.

The nature of the transition from acute to chronic pain still eludes explanation, but chronic pain resulting from surgery provides a natural experiment that invites clinical epidemiological investigation and basic scientific inquiry into the mechanisms of this transition. The primary purpose of this article is to review current knowledge and hypotheses on the transition from acute to persistent postsurgical pain, summarizing literature on clinical epidemiological studies of persistent postsurgical pain development, as well as basic neurophysiological studies targeting mechanisms in the periphery, spinal cord, and brain. The second purpose of this article is to integrate theory, information, and causal reasoning in these areas. Conceptual mapping reveals 5 classes of hypotheses pertaining to pain. These propose that chronic pain results from: 1) persistent noxious signaling in the periphery; 2) enduring maladaptive neuroplastic changes at the spinal dorsal horn and/or higher central nervous system structures reflecting a multiplicity of factors, including peripherally released neurotrophic factors and interactions between neurons and microglia; 3) compromised inhibitory modulation of noxious signaling in medullary-spinal pathways; 4) descending facilitatory modulation; and 5) maladaptive brain remodeling in function, structure, and connectivity. The third purpose of this article is to identify barriers to progress and review opportunities for advancing the field. This review reveals a need for a concerted, strategic effort toward integrating clinical epidemiology, basic science research, and current theory about pain mechanisms to hasten progress toward understanding, managing, and preventing persistent postsurgical pain. PERSPECTIVE: The development of chronic pain after surgery is a major clinical problem that provides an opportunity to study the transition from acute to chronic pain at epidemiologic and basic science levels. Strategic, coordinated, multidisciplinary research efforts targeting mechanisms of pain chronification can to help minimize or eliminate persistent postsurgical pain.

Testing Assumptions in Human Pain Models: Psychophysical Differences Between First and Second Pain.

Acute pain arises from activation of myelinated (A delta) and unmyelinated (C) nociceptive afferents, leading to first (A-fiber) or second (C-fiber) pain sensations. The current study sought to investigate first and second pain within glabrous and hairy skin sites in human upper limbs. Fifty healthy adults (25 male/25 female, 18-30 years old, mean = 20.5 ± 1.4 years) participated in a psychophysical study investigating electronically rated, thermal first and second pain sensations within the glabrous skin at the palm and hairy skin of the forearm. Repeated measures analysis of variance indicated that the threshold for first pain was lower (more sensitive) than for second pain (P = .004), for glabrous as well as hairy skin, and thresholds at glabrous skin were higher than for hairy skin (P = .001). Hairy skin presented a steeper slope for testing, whereas there were no differences in slope between first and second pain. The study findings support assumptions associated with mechanistic differences between first and second pain sensations, while offering a novel method for producing first and second pain with the same thermal stimulus. Efforts to understand abnormalities among people with clinical pain and development of new therapeutic agents will benefit from specific psychophysical methods. PERSPECTIVE: This article presents a novel method for directly comparing first and second pain within the same thermal stimulus. The ability to directly compare first and second pain sensations can aid in understanding pain abnormalities in clinical pain and development of therapeutic aids.

Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation.

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0-100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain.

Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers.

BACKGROUND: Pain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject's real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set-point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions. METHODS: We used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set-point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100. RESULTS: Sixteen healthy individuals (mean age = 21.6 ± 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r's = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set-point. CONCLUSIONS: The present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods.

Comparison of operant escape and reflex tests of nociceptive sensitivity.

Testing of reflexes such as flexion/withdrawal or licking/guarding is well established as the standard for evaluating nociceptive sensitivity and its modulation in preclinical investigations of laboratory animals. Concerns about this approach have been dismissed for practical reasons - reflex testing requires no training of the animals; it is simple to instrument; and responses are characterized by observers as latencies or thresholds for evocation. In order to evaluate this method, the present review summarizes a series of experiments in which reflex and operant escape responding are compared in normal animals and following surgical models of neuropathic pain or pharmacological intervention for pain. Particular attention is paid to relationships between reflex and escape responding and information on the pain sensitivity of normal human subjects or patients with pain. Numerous disparities between results for reflex and operant escape measures are described, but the results of operant testing are consistent with evidence from humans. Objective reasons are given for experimenters to choose between these and other methods of evaluating the nociceptive sensitivity of laboratory animals.

Characteristics of sensitization associated with chronic pain conditions.

OBJECTIVES: To describe and understand varieties and characteristics of sensitization contributing to hyperalgesia in participants with chronic pain conditions. METHODS: Thermal stimulation was delivered to the face, forearm, and calf of pain-free participants and individuals with irritable bowel syndrome, temporomandibular pain disorder (TMD), and fibromyalgia syndrome (FM). Three-second contacts by a preheated thermode occurred at 30-second intervals in ascending and then in descending series (0.7°C steps). RESULTS: Thermal pain ratings during ascending series were greater at each site in individuals diagnosed with chronic pain. Intense pain at the time of testing further enhanced the ratings at all sites, but mild or moderate clinical pain did not have this effect. Thermal pain in all participants was greater during descending series compared with the ascending series of arm and leg stimulation. The hypersensitivity during the descending series was comparable in pain-free, FM and TMD participants but was increased in duration for arm or leg stimulation of FM participants. DISCUSSION: The widespread sensitization for irritable bowel syndrome and TMD participants does not rely on mechanisms of spatial and temporal summation often invoked to explain widespread hyperalgesia associated with chronic pain. Increased sensitivity during descending series of stimulation of an arm or leg but not the face indicates a propensity for sensitization of nociceptive input to the spinal cord. Abnormally prolonged sensitization for FM participants reveals a unique influence of widespread chronic pain referred to deep somatic tissues.

Effects of gabapentin on thermal sensitivity following spinal nerve ligation or spinal cord compression.

Neuropathic pain challenges healthcare professionals and researchers to develop new strategies of treatment and experimental models to better understand the pathophysiology of this condition. In the present study, the efficacy of gabapentin on thermal sensitivity following spinal nerve ligation and spinal cord compression was evaluated. The method of behavioral assessment was a well-validated cortically dependent operant escape task. Spinal nerve ligation produced peripheral neuropathic pain whereas spinal cord compression, achieved with an expanding polymer placed extradurally, produced a condition of central neuropathic pain. Changes in thermal sensitivity were also observed in animals undergoing nerve ligation surgery without nerve injury. Gabapentin (50 and 100 mg/kg) significantly reduced thermal sensitivity to 10 and 44.5 °C in surgically naive animals as well as those undergoing spinal nerve ligation and spinal cord compression. In conclusion, an operant method of behavioral assessment was used to show that spinal nerve ligation and spinal cord compression produced increases in sensitivity to noxious cold and heat stimuli. A decrease in thermal sensitivity was observed following administration of gabapentin. The results achieved with these methods are consistent with the clinical profile of gabapentin in treating conditions of neuropathic pain.

Excitotoxic injury to thoracolumbar gray matter alters sympathetic activation and thermal pain sensitivity.

Studies of humans, monkeys and rodents have implicated combined gray and white matter damage as important for development of chronic pain following spinal cord injury (SCI). Below-level chronic pain and hyperalgesia following injury to the spinal white matter, including the spinothalamic tract (STT), can be enhanced by excitotoxic influences within the gray matter at the site of SCI. Also, excitotoxic injury of thoracic gray matter without interruption of the STT results in below-level heat hyperalgesia. The present study evaluates the possibility that thoracolumbar gray matter injury increases sensitivity to nociceptive heat stimulation by altering spinal sympathetic outflow. Thermal preferences of rats for heat (45 °C) versus cold (15 °C) were evaluated before and after thoracolumbar injections of quisqualic acid (QUIS). A pre-injury preference for heat changed to a post-injury preference for cold. Systemic activation of the sympathetic nervous system by restraint stress decreased the heat preference pre-injury and increased the cold preference post-injury. The heat aversive effect of stress was magnified and prolonged post-injury, compared to pre-injury. Also, peripheral sympathetic activation by nociceptive stimulation was evaluated pre- and post-injury by measuring thermal transfer through a hindpaw during stimulation with 44.5 °C. Skin temperature recordings revealed enhanced sympathetic activation by nociceptive heat stimulation following spinal QUIS injury. However, increased sympathetic activation with peripheral vasoconstriction should enhance cold aversion, in contrast to the observed increase in heat aversion. Thus, peripheral sympathetic vasoconstriction can be ruled out as a mechanism for heat hyperalgesia following excitotoxic gray matter injury.

Evaluation of lateral spinal hemisection as a preclinical model of spinal cord injury pain.

Operant escape from nociceptive thermal stimulation of 13 Long-Evans rats was compared before and after lateral spinal hemisection, to determine whether this lesion configuration provides an appropriate preclinical model of the hyperalgesia that can be associated with human spinal cord injury. Escape from 44 °C and from 47 °C stimulation was not affected following sham spinal surgery but was significantly reduced over 20 weeks of postoperative testing following lateral spinal hemisection. This result is opposite to previous reports of enhanced reflex withdrawal in response to thermal stimulation of rats following lateral spinal hemisection. In addition, the latency of reflexive lick/guard responses to 44 °C was increased and the duration of lick/guard responding was decreased in the present study (hyporeflexia). Thus, previous assessments of simple withdrawal reflexes have described a hyperreflexia following lateral spinal hemisection that was not replicated by lick/guard testing, and postoperative escape responding revealed hypoalgesia rather than the increased pain sensitivity expected in a model of chronic pain.

Relationships between the intensity and duration of Peltier heat stimulation and pain magnitude.

Ramp-and-hold heat stimulation with a Peltier thermode is a standard procedure for quantitative sensory testing of human pain sensitivity. Because myelinated and unmyelinated nociceptive afferents respond preferentially to changing and steady temperatures, respectively, ramp-and-hold heat stimulation could assess processing of input from A-delta nociceptors early and C nociceptors late during prolonged thermal stimulation. In order to evaluate the progression from dynamic change to a steady temperature during prolonged Peltier stimulation, recordings of temperatures at the probe-skin interface were obtained. First, recordings of temperature during contact-and-hold stimulation (solenoid powered delivery of a preheated thermode to the skin) provided an evaluation of heat dissipation from the beginning of stimulation, uncontaminated by ramping. The heat-sink effect lasted up to 8 s and accounted in part for a slow increase in pain intensity for stimulus durations of 1-16 s and stimulus intensities of 43-59 °C. Recordings during longer periods of stimulation showed that feedback-controlled Peltier stimulation generated oscillations in temperature that were tracked for up to 75 s by subjects' continuous ratings of pain. During 120-s trials, sensitization of pain was observed over 45 s after the oscillations subsided. Thus, long-duration stimulation can be utilized to evaluate sensitization, presumably of C nociception, when not disrupted by oscillations in thermode temperature (e.g., those inherent to feedback control of Peltier stimulation). In contrast, sensitization was not observed during 130.5 s of stimulation with alternately increasing and decreasing temperatures that repeatedly activated A-delta nociceptors.

Role of primary somatosensory cortex in the coding of pain.

The intensity and submodality of pain are widely attributed to stimulus encoding by peripheral and subcortical spinal/trigeminal portions of the somatosensory nervous system. Consistent with this interpretation are studies of surgically anesthetized animals, demonstrating that relationships between nociceptive stimulation and activation of neurons are similar at subcortical levels of somatosensory projection and within the primary somatosensory cortex (in cytoarchitectural areas 3b and 1 of somatosensory cortex, SI). Such findings have led to characterizations of SI as a network that preserves, rather than transforms, the excitatory drive it receives from subcortical levels. Inconsistent with this perspective are images and neurophysiological recordings of SI neurons in lightly anesthetized primates. These studies demonstrate that an extreme anterior position within SI (area 3a) receives input originating predominantly from unmyelinated nociceptors, distinguishing it from posterior SI (areas 3b and 1), long recognized as receiving input predominantly from myelinated afferents, including nociceptors. Of particular importance, interactions between these subregions during maintained nociceptive stimulation are accompanied by an altered SI response to myelinated and unmyelinated nociceptors. A revised view of pain coding within SI cortex is discussed, and potentially significant clinical implications are emphasized.

A mechanism-based approach to prevention of and therapy for fibromyalgia.

Fibromyalgia syndrome (FMS) is characterized by pain referred to deep tissues. Diagnosis and treatment of FMS are complicated by a variable coexistence with regional pain, fatigue, sleep disruption, difficulty with mentation, and depression. The widespread, deep pain of FMS can be a consequence of chronic psychological stress with autonomic dysregulation. Stress acts centrally to facilitate pain and acts peripherally, via sympathetic vasoconstriction, to establish painful muscular ischemia. FMS pain, with or without a coexistent regional pain condition, is stressful, setting up a vicious circle of reciprocal interaction. Also, stress interacts reciprocally with systems of control over depression, mentation, and sleep, establishing FMS as a multiple-system disorder. Thus, stress and the ischemic pain it generates are fundamental to the multiple disorders of FMS, and a therapeutic procedure that attenuates stress and peripheral vasoconstriction should be highly beneficial for FMS. Physical exercise has been shown to counteract peripheral vasoconstriction and to attenuate stress, depression, and fatigue and improve mentation and sleep quality. Thus, exercise can interrupt the reciprocal interactions between psychological stress and each of the multiple-system disorders of FMS. The large literature supporting these conclusions indicates that exercise should be considered strongly as a first-line approach to FMS therapy.

Sex differences in effects of excitotoxic spinal injury on below-level pain sensitivity.

Effects of excitotoxic injury to the thoracic gray matter on sensitivity to below-level nociceptive stimulation were evaluated for female and male Long-Evans rats. Operant escape and lick/guard (L/G) reflex responses to thermal stimulation were evaluated before and for 13-15 weeks after: 1) injections of quisqualic acid (QUIS) into the thoracic gray matter (T8-9), 2) laminectomy and spinal exposure and penetration without injection (sham) or 3) no surgical procedure (control). L/G responding to heat stimulation (44 °C) was unaffected for females and males following thoracic QUIS injections. Similarly, male escape performance was not significantly altered for 44 °C or 10 °C stimulation after QUIS injections or sham surgery. However, escape testing following QUIS and sham injections revealed increased heat sensitivity (44 °C) and decreased cold sensitivity (10 °C) for females. This selective effect is indicative of altered sympathetic activation by the thoracic injections. The effect of sham surgery suggests that female rats are vulnerable to ischemic injury during exposure and manipulation of the spinal cord. Escape from nociceptive heat and cold sensitivity of control males and females was unchanged over 13-15 weeks of testing.

Central sensitization in the trigeminal nucleus caudalis produced by a conjugate of substance P and the A subunit of cholera toxin.

UNLABELLED: Individuals with chronic craniofacial pain experience symptoms that are consistent with central sensitization. In fact, central sensitization may constitute the major disease process in these conditions, particularly if the original injury has healed or the condition is idiopathic. To understand central sensitization we have developed a conjugate of substance P and cholera toxin (SP-CTA). SP-CTA is selectively taken up by cells that express neurokinin receptors. Twenty-four hours following intracisternal administration of SP-CTA, wild-type rats and mice demonstrated signs of persistent background nociception, but when tested for facial cold sensitivity, they did not differ from controls. However, treating the SP-CTA-injected animals with naloxone exposed cold hypersensitivity in the face. Mu-opioid receptor knockout mice treated with SP-CTA demonstrated hypersensitivity without naloxone treatment. These findings suggest that central sensitization leads to activation of an endogenous opioid system. The data also demonstrate that the intracisternal administration of SP-CTA in rodents is a useful model for studying central sensitization as a disease process without having to induce a peripheral injury. PERSPECTIVE: Central sensitization is a concern in many craniofacial pain conditions. In this project, we utilize a conjugate of substance P and the catalytic subunit of cholera toxin to induce central sensitization in the nucleus caudalis of rodents. The data indicate that the injected animals become hypersensitive in the face.